An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson's disease.
An antisense Alu transposon insertion/deletion polymorphism of ALDH1A1 may functionally associate with Parkinson's disease.
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DOI：
10.1186/s12877-022-03132-1
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发表时间：
2022-05-16
期刊：
影响因子：
4.1
通讯作者：
Zhu, Jian-Hong
中科院分区：
文献类型：
--
作者：
Fan, Hui-Hui;Zheng, Jing;Huang, Xiao-Ya;Wu, Ke-Yun;Cui, Lei;Dong, Hao-Jia;Wang, Zhen;Zhang, Xiong;Zhu, Jian-Hong
醛脱氢酶1（由ALDH1A1编码）已被证明可通过减少多巴胺的有毒代谢产物来预防帕金森病（PD）。在此我们揭示了ALDH1A1内含子4中的一个反义Alu元件插入/缺失多态性，并假设它可能在帕金森病中起作用。
我们招募了一个由488名帕金森病患者和515名对照组成的中国汉族队列，以在先前对标签单核苷酸多态性的研究之后验证Alu插入/缺失多态性，在该研究中，rs7043217被证明与帕金森病显著相关。对Alu元件插入进行了功能分析。
ALDH1A1的Alu元件被鉴定为Yb8亚家族的一个变体，并被命名为Yb8c4。反义Yb8c4插入/缺失多态性（分别命名为Yb8c4ins和Yb8c4del）似乎与rs7043217完全连锁不平衡，并被验证与帕金森病易感性显著相关，其中Yb8c4ins为风险等位基因（P = 0.030，OR = 1.224，95%CI = 1.020 - 1.470）。多项功能分析，包括携带者血细胞中ALDH1A1 mRNA的表达，以及增强型绿色荧光蛋白（EGFP）和荧光素酶报告基因，表明Yb8c4ins对基因转录具有抑制活性。机制探索表明，Yb8c4ins不会引起ALDH1A1的CpG甲基化和mRNA剪接的变化，也未出现转录因子的结合。
我们的结果巩固了ALDH1在帕金森病发病机制中的参与。Yb8c4多态性可能是与其连锁不平衡相关的单核苷酸多态性的一种功能性结果。
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Aldehyde dehydrogenase 1 (encoded by ALDH1A1) has been shown to protect against Parkinson’s disease (PD) by reducing toxic metabolites of dopamine. We herein revealed an antisense Alu element insertion/deletion polymorphism in intron 4 of ALDH1A1, and hypothesized that it might play a role in PD. A Han Chinese cohort comprising 488 PD patients and 515 controls was recruited to validate the Alu insertion/deletion polymorphism following a previous study of tag-single nucleotide polymorphisms, where rs7043217 was shown to be significantly associated with PD. Functional analyses of the Alu element insertion were performed. The Alu element of ALDH1A1 was identified to be a variant of Yb8 subfamily and termed as Yb8c4. The antisense Yb8c4 insertion/deletion polymorphism (named asYb8c4ins and asYb8c4del, respectively) appeared to be in a complete linkage disequilibrium with rs7043217 and was validated to be significantly associated with PD susceptibility with asYb8c4ins serving as a risk allele (P = 0.030, OR = 1.224, 95% CI = 1.020–1.470). Multiple functional analyses including ALDH1A1 mRNA expression in blood cells of carriers, and reporters of EGFP and luciferase showed that the asYb8c4ins had a suppressive activity on gene transcription. Mechanistic explorations suggested that the asYb8c4ins induced no changes in CpG methylation and mRNA splicing of ALDH1A1 and appeared no binding of transcription factors. Our results consolidate an involvement of ALDH1 in PD pathogenesis. The asYb8c4 polymorphism may be a functional output of its linkage disequilibrium-linked single nucleotide polymorphisms. The online version contains supplementary material available at 10.1186/s12877-022-03132-1.
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DOI：
10.1074/jbc.ra118.005439
发表时间：
2018-11-23
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Graham WJ 5th;Putnam CD;Kolodner RD
通讯作者：
Kolodner RD
影响因子：
15.1
作者：
Molochnikov L;Rabey JM;Dobronevsky E;Bonucelli U;Ceravolo R;Frosini D;Grünblatt E;Riederer P;Jacob C;Aharon-Peretz J;Bashenko Y;Youdim MB;Mandel SA
通讯作者：
Mandel SA
人类外周血单核细胞中七个候选基因的表达水平及其与先兆子痫的相关性。
影响因子：
1.5
作者：
Martinez-Fierro ML;Garza-Veloz I;Carrillo-Sanchez K;Martinez-Gaytan V;Cortes-Flores R;Ochoa-Torres MA;Guerrero GG;Rodriguez-Sanchez IP;Cancela-Murrieta CO;Zamudio-Osuna M;Badillo-Almaraz JI;Castruita-De la Rosa C
通讯作者：
Castruita-De la Rosa C
影响因子：
8.8
作者：
Choudhary B;Marx O;Norris AD
通讯作者：
Norris AD
影响因子：
11
作者：
HUGHES, AJ;DANIEL, SE;LEES, AJ
通讯作者：
LEES, AJ